Rare monogenic forms of common diseases have provided key fundamental insights about common disease. However, genetic, environmental, and stochastic elements influence risk for disease. Familial hypercholesterolemia (FH), an autosomal dominant disorder afflicting 1 in 250 linked to severe increases in LDL cholesterol and premature coronary heart disease (CHD) risk, is an ideal model to characterize modifiers of disease. Despite the presence of a strong genetic driver of hypercholesterolemia from FH mutations, we recently observed that half do not have the expected severe hypercholesterolemia. In this proposal, we outline several methods to discover and dissect the genetic and non-genetic factors influencing CHD risk conferred by FH mutations in humans and determine whether knowledge of these factors can improve risk discrimination among those with FH mutations. Our approach harnesses several multi-dimensional datasets: whole genome sequences, metabolomics, and cross-sectional and longitudinal cardiovascular phenotypes. In Aim 1, we will aggregate and curate 75,000 deep (30X) whole genome sequences and cardiovascular phenotypes. In Aim 2, we will discover genetic and non-genetic modifiers of LDL cholesterol and CHD risk in FH and evaluate their metabolomic consequences. In Aim 3, we will develop a method incorporating genetics and longitudinal non- genetic exposures for CHD risk stratification among ~4,000 with FH mutations in the Million Veteran Program. In addition to the proposed Aims, this five-year proposal outlines a comprehensive strategy for the principal investigator's (PI's) scientific and professional development in academic cardiovascular medicine. The research strategy builds upon the PI's prior research experience and clinical training. In addition to an undergraduate degree in Molecular Biology and master's degree in Biomedical Informatics, he completed post- graduate medical training in Internal Medicine and Cardiovascular Medicine. He recently developed a new preventive/genetic cardiology clinic focusing on the evaluation and management of those with or a family history of premature CHD, including those with FH, at Massachusetts General Hospital (MGH). This proposal now focuses on expanding his scientific skills in human genetics and genomics into new domains: integrative genomics, statistical genetics, clinical informatics, and risk modeling. The career development goals will be at achieved through a multi-faceted approach involving mentorship, collaboration, didactic coursework, conferences, and scientific investigation. This work will take place in a unique training environment comprised of MGH and the Broad Institute. Successful completion of this career development award will result in improved fundamental understanding of the determinants of CHD, result in the PI's transition to an independent physician-scientist, and provide a solid foundation from which he will apply for R01-level funding.